PMID- 28007903
OWN - NLM
STAT- MEDLINE
DCOM- 20170926
LR  - 20211204
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 26
IP  - 1
DP  - 2017 Jan 1
TI  - Autophagy activators suppress cystogenesis in an autosomal dominant polycystic 
      kidney disease model.
PG  - 158-172
LID - 10.1093/hmg/ddw376 [doi]
AB  - Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in 
      either PKD1 or PKD2. It is one of the most common heritable human diseases with 
      eventual development of renal failure; however, effective treatment is lacking. 
      While inhibition of mechanistic target of rapamycin (mTOR) effectively slows cyst 
      expansions in animal models, results from clinical studies are controversial, 
      prompting further mechanistic studies of mTOR-based therapy. Here, we aim to 
      establish autophagy, a downstream pathway of mTOR, as a new therapeutic target 
      for PKD. We generated zebrafish mutants for pkd1 and noted cystic kidney and mTOR 
      activation in pkd1a mutants, suggesting a conserved ADPKD model. Further 
      assessment of the mutants revealed impaired autophagic flux, which was conserved 
      in kidney epithelial cells derived from both Pkd1-null mice and ADPKD patients. 
      We found that inhibition of autophagy by knocking down the core autophagy protein 
      Atg5 promotes cystogenesis, while activation of autophagy using a specific 
      inducer Beclin-1 peptide ameliorates cysts in the pkd1a model. Treatment with 
      compound autophagy activators, including mTOR-dependent rapamycin as well as 
      mTOR-independent carbamazepine and minoxidil, markedly attenuated cyst formation 
      and restored kidney function. Finally, we showed that combination treatment with 
      low doses of rapamycin and carbamazepine was able to attenuate cyst formation as 
      effectively as a single treatment with a high dose of rapamycin alone. In 
      summary, our results suggested a modifying effect of autophagy on ADPKD, 
      established autophagy activation as a novel therapy for ADPKD, and presented 
      zebrafish as an efficient vertebrate model for developing PKD therapeutic 
      strategies.
CI  - (c) The Author 2016. Published by Oxford University Press. All rights reserved. For 
      Permissions, please email: journals.permissions@oup.com.
FAU - Zhu, Ping
AU  - Zhu P
AD  - Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, 
      USA.
FAU - Sieben, Cynthia J
AU  - Sieben CJ
AD  - Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, 
      USA.
FAU - Xu, Xiaolei
AU  - Xu X
AD  - Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, 
      USA.
AD  - Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA.
FAU - Harris, Peter C
AU  - Harris PC
AD  - Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.
FAU - Lin, Xueying
AU  - Lin X
AD  - Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, 
      USA.
LA  - eng
GR  - P30 DK090728/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (Autophagy-Related Protein 5)
RN  - 0 (TRPP Cation Channels)
RN  - 0 (polycystic kidney disease 1 protein)
RN  - 33CM23913M (Carbamazepine)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
CIN - Nat Rev Nephrol. 2017 Mar;13(3):134. PMID: 28090082
MH  - Animals
MH  - Autophagy/*drug effects
MH  - Autophagy-Related Protein 5/metabolism
MH  - Carbamazepine/pharmacology
MH  - Cells, Cultured
MH  - Disease Models, Animal
MH  - Embryo, Nonmammalian/drug effects/metabolism/pathology
MH  - Epithelial Cells/drug effects/metabolism/pathology
MH  - Mice
MH  - Mice, Knockout
MH  - Polycystic Kidney, Autosomal Dominant/metabolism/pathology/*prevention & control
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - TRPP Cation Channels/*physiology
MH  - Zebrafish
PMC - PMC6251521
EDAT- 2016/12/23 06:00
MHDA- 2017/09/28 06:00
PMCR- 2018/01/01
CRDT- 2016/12/24 06:00
PHST- 2016/08/08 00:00 [received]
PHST- 2016/10/27 00:00 [accepted]
PHST- 2016/12/23 06:00 [pubmed]
PHST- 2017/09/28 06:00 [medline]
PHST- 2016/12/24 06:00 [entrez]
PHST- 2018/01/01 00:00 [pmc-release]
AID - ddw376 [pii]
AID - 10.1093/hmg/ddw376 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2017 Jan 1;26(1):158-172. doi: 10.1093/hmg/ddw376.